Under certain circumstances, polymorphonuclear leukocyte (PMN) recruitment to sites of airway inflammation can lead to tissue damage via the production of proteases, reactive oxygen species, proinflammatory cytokines and chemokines. PMN are thought to play a role in acute lung diseases as well as chronic obstructive pulmonary diseases and contribute to inflammation and lung damage in cystic fibrosis. We herein describe a novel pathway of PMN influx and damage to the airways that may represent a new therapeutic target for certain pulmonary diseases. In particular, when collagen is chemically or enzymatically degraded a tripeptide, PGP, is generated that is chemotactic for PMN in vitro. In vivo, airway exposure to PGP elicits a marked influx of PMN, but not monocytes. More chronic airway exposure to PGP causes alveolar enlargement and right ventricular hypertrophy. Using electrospray ionization-liquid chromatography- mass spectrometry (ESI-LC-MS/MS), PGP is detected in the airways of animals exposed to endotoxin (LPS). In addition, the peptide substantially contributes to PMN influx into inflamed airways. The chemotactic activity of PGP apparently results from an extraordinary structural relatedness to a receptor binding motif of CXC chemokines, like IL-8 that contain this sequence or a close analog. We have designed a novel peptide with the sequence arginine-threonine-arginine (RTR) that binds PGP and potently blocks the peptide's in vitro chemotactic activity and in vivo pathophysiologic effects. RTR also inhibits CXC chemokine activity apparently as a result of the shared structure between PGP and the chemokines. Thus, RTR represents a potential therapeutic agent that can block both the chemokine and PGP pathways of inflammation. These results have led to the following goals for this application. 1. Determine whether PGP binds CXC chemokine receptors (R) and activates CXCR coupled effector pathways. 2. Evaluate the spectrum of PGP-containing peptides that are produced during airway inflammation and whether PGP recruits PMN to the airways during acute inflammation. 3. Determine whether PMN are necessary for PGP-mediated alveolar enlargement and right ventricular hypertrophy. 4. Evaluate the relative pathophysiologic roles of PGP as compared to CXC chemokines in a model of persistent LPS-mediated pulmonary disease. 5. Test RTR as an antagonist of the PGP and CXC chemokine pathways in the LPS-mediated pulmonary disease model. [unreadable] [unreadable] [unreadable]